The branch is focusing on identifying the role of neutrophil extracellular traps in the development of autoimmune responses and end-organ damage in systemic diseases including lupus (SLE), rheumatoid arthritis (RA) and systemic vasculitides (AAV). During this year, our group demonstrated in various animal models the role that NETs may play in vivo with regards to atherogenesis, renal damage, type I Interferon production and skin manifestations in mouse models of lupus and atherosclerosis. We have identified peptidylarginine deiminase-IV as a potential therapeutic target in these diseases, given its role in NET formation. Furthermore, we characterized NETs as an important in vivo source of the oxidative enzyme machinery that contributes to modifications of lipoprotein promoting atherogenesis. Lupus patients have evidence of aberrant HDL, which is highly oxidized and displays abnormal function, as measured by reverse cholesterol transport. We identified enzymes externalized in NETs as a highly competent machinery leading to HDL oxidation. Abrogation of NET formation in vivo significantly reduces HDL oxidation. Following a bench to bedside approach we are in the process of establishing a well-characterized cardiovascular lupus cohort which is being followed prospectively for identification of novel biomarkers that predict progression of vascular inflammation, endothelial dysfunction and premature vascular events. We are using sophisticated imaging and functional vascular assays to quantify these abnormalities in lupus patients. We have also reported that NETs are a source of citrullinated autoantigens and this phenomenon may be important in the initiation and perpetuation of aberrant inflammatory responses in rheumatoid arthritis. We found that NET formation is enhanced in RA both in blood and synovium, NETs externalize citrullinated proteins that are known to be important autoantigens in RA. Autoantibodies to citrullinate proteins in turn enhance NET formation. NETs promote synovial fibroblast inflammation. Ongoing work is attempting to further elucidate the interplay between NETs and synovial fibroblasts as an amplification mechanism in inflammatory arthritides.

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1
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2014
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Arthritis, Musculoskeletal, Skin Dis
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Liu, Yudong; Seto, Nickie L; Carmona-Rivera, Carmelo et al. (2018) Accelerated model of lupus autoimmunity and vasculopathy driven by toll-like receptor 7/9 imbalance. Lupus Sci Med 5:e000259
Carlucci, Philip M; Purmalek, Monica M; Dey, Amit K et al. (2018) Neutrophil subsets and their gene signature associate with vascular inflammation and coronary atherosclerosis in lupus. JCI Insight 3:
Irizarry-Caro, Jorge A; Carmona-Rivera, Carmelo; Schwartz, Daniella M et al. (2018) Brief Report: Drugs Implicated in Systemic Autoimmunity Modulate Neutrophil Extracellular Trap Formation. Arthritis Rheumatol 70:468-474
Gupta, Sarthak; Chan, Diana W; Zaal, Kristien J et al. (2018) A High-Throughput Real-Time Imaging Technique To Quantify NETosis and Distinguish Mechanisms of Cell Death in Human Neutrophils. J Immunol 200:869-879
Barrera-Vargas, Ana; Gómez-Martín, Diana; Carmona-Rivera, Carmelo et al. (2018) Differential ubiquitination in NETs regulates macrophage responses in systemic lupus erythematosus. Ann Rheum Dis 77:944-950
Liu, Yudong; Carmona-Rivera, Carmelo; Moore, Erica et al. (2018) Myeloid-Specific Deletion of Peptidylarginine Deiminase 4 Mitigates Atherosclerosis. Front Immunol 9:1680
Demoruelle, M Kristen; Bowers, Emily; Lahey, Lauren J et al. (2018) Antibody Responses to Citrullinated and Noncitrullinated Antigens in the Sputum of Subjects With Rheumatoid Arthritis and Subjects at Risk for Development of Rheumatoid Arthritis. Arthritis Rheumatol 70:516-527
Carmona-Rivera, Carmelo; Bicker, Kevin L; Thompson, Paul R et al. (2018) Response to comment on ""Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis"". Sci Immunol 3:
Liu, Yudong; Kaplan, Mariana J (2018) Cardiovascular disease in systemic lupus erythematosus: an update. Curr Opin Rheumatol 30:441-448
Grayson, Peter C; Alehashemi, Sara; Bagheri, Armin A et al. (2018) 18 F-Fluorodeoxyglucose-Positron Emission Tomography As an Imaging Biomarker in a Prospective, Longitudinal Cohort of Patients With Large Vessel Vasculitis. Arthritis Rheumatol 70:439-449

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